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Background Excessive respiratory muscle effort during mechanical ventilation may cause patient self-inflicted lung injury and load-induced diaphragm myotrauma, but there are no non-invasive methods to reliably detect elevated transpulmonary driving pressure and elevated respiratory muscle effort during assisted ventilation. We hypothesized that the swing in airway pressure generated by respiratory muscle effort under assisted ventilation when the airway is briefly occluded (Δ P occ ) could be used as a highly feasible non-invasive technique to screen for these conditions. Methods Respiratory muscle pressure ( P mus ), dynamic transpulmonary driving pressure (Δ P L,dyn , the difference between peak and end-expiratory transpulmonary pressure), and Δ P occ were measured daily in mechanically ventilated patients in two ICUs in Toronto, Canada. A conversion factor to predict Δ P L,dyn and P mus from Δ P occ was derived and validated using cross-validation. External validity was assessed in an independent cohort (Nanjing, China). Results Fifty-two daily recordings were collected in 16 patients. In this sample, P mus and Δ P L were frequently excessively high: P mus exceeded 10 cm H 2 O on 84% of study days and Δ P L,dyn exceeded 15 cm H 2 O on 53% of study days. Δ P occ measurements accurately detected P mus > 10 cm H 2 O (AUROC 0.92, 95% CI 0.83–0.97) and Δ P L,dyn  > 15 cm H 2 O (AUROC 0.93, 95% CI 0.86–0.99). In the external validation cohort ( n  = 12), estimating P mus and Δ P L,dyn from Δ P occ measurements detected excessively high P mus and Δ P L,dyn with similar accuracy (AUROC ≥ 0.94). Conclusions Measuring Δ P occ enables accurate non-invasive detection of elevated respiratory muscle pressure and transpulmonary driving pressure. Excessive respiratory effort and transpulmonary driving pressure may be frequent in spontaneously breathing ventilated patients.

Background Insufficient or excessive respiratory effort during acute hypoxemic respiratory failure (AHRF) increases the risk of lung and diaphragm injury. We sought to establish whether respiratory effort can be optimized to achieve lung- and diaphragm-protective (LDP) targets (esophageal pressure swing − 3 to − 8 cm H 2 O; dynamic transpulmonary driving pressure ≤ 15 cm H 2 O) during AHRF. Methods In patients with early AHRF, spontaneous breathing was initiated as soon as passive ventilation was not deemed mandatory. Inspiratory pressure, sedation, positive end-expiratory pressure (PEEP), and sweep gas flow (in patients receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO)) were systematically titrated to achieve LDP targets. Additionally, partial neuromuscular blockade (pNMBA) was administered in patients with refractory excessive respiratory effort. Results Of 30 patients enrolled, most had severe AHRF; 16 required VV-ECMO. Respiratory effort was absent in all at enrolment. After initiating spontaneous breathing, most exhibited high respiratory effort and only 6/30 met LDP targets. After titrating ventilation, sedation, and sweep gas flow, LDP targets were achieved in 20/30. LDP targets were more likely to be achieved in patients on VV-ECMO (median OR 10, 95% CrI 2, 81) and at the PEEP level associated with improved dynamic compliance (median OR 33, 95% CrI 5, 898). Administration of pNMBA to patients with refractory excessive effort was well-tolerated and effectively achieved LDP targets. Conclusion Respiratory effort is frequently absent  under deep sedation but becomes excessive when spontaneous breathing is permitted in patients with moderate or severe AHRF. Systematically titrating ventilation and sedation can optimize respiratory effort for lung and diaphragm protection in most patients. VV-ECMO can greatly facilitate the delivery of a LDP strategy. Trial registration : This trial was registered in Clinicaltrials.gov in August 2018 (NCT03612583).

Background Muscle atrophy is a common consequence of the loss of innervation and is accompanied by mitochondrial dysfunction. Mitophagy is the adaptive process through which damaged mitochondria are removed via the lysosomes, which are regulated in part by the transcription factor TFE3. The role of lysosomes and TFE3 are poorly understood in muscle atrophy, and the effect of biological sex is widely underreported. Methods Wild-type (WT) mice, along with mice lacking TFE3 (KO), a transcriptional regulator of lysosomal and autophagy-related genes, were subjected to unilateral sciatic nerve denervation for up to 7 days, while the contralateral limb was sham-operated and served as an internal control. A subset of animals was treated with colchicine to capture mitophagy flux. Results WT females exhibited elevated oxygen consumption rates during active respiratory states compared to males, however this was blunted in the absence of TFE3. Females exhibited higher mitophagy flux rates and greater lysosomal content basally compared to males that was independent of TFE3 expression. Following denervation, female mice exhibited less muscle atrophy compared to male counterparts. Intriguingly, this sex-dependent muscle sparing was lost in the absence of TFE3. Denervation resulted in 45% and 27% losses of mitochondrial content in WT and KO males respectively, however females were completely protected against this decline. Decreases in mitochondrial function were more severe in WT females compared to males following denervation, as ROS emission was 2.4-fold higher. In response to denervation, LC3-II mitophagy flux was reduced by 44% in females, likely contributing to the maintenance of mitochondrial content and elevated ROS emission, however this response was dysregulated in the absence of TFE3. While both males and females exhibited increased lysosomal content following denervation, this response was augmented in females in a TFE3-dependent manner. Conclusions Females have higher lysosomal content and mitophagy flux basally compared to males, likely contributing to the improved mitochondrial phenotype. Denervation-induced mitochondrial adaptations were sexually dimorphic, as females preferentially preserve content at the expense of function, while males display a tendency to maintain mitochondrial function. Our data illustrate that TFE3 is vital for the sex-dependent differences in mitochondrial function, and in determining the denervation-induced atrophy phenotype.

Abstract Study Objectives To investigate the risk of in-hospital falls among patients receiving medications commonly used for insomnia in the hospital setting. Methods Retrospective cohort study of all adult hospitalizations to a large academic medical center from January, 2007 to July, 2013. We excluded patients admitted for a primary psychiatric disorder. Medication exposures of interest, defined by pharmacy charges, included benzodiazepines, non-benzodiazepine benzodiazepine receptor agonists, trazodone, atypical antipsychotics, and diphenhydramine. In-hospital falls were ascertained from an online patient safety reporting system. Results Among the 225,498 hospitalizations (median age = 57 years; 57.9% female) in our cohort, 84,911 (37.7%) had exposure to at least one of the five medication classes of interest; benzodiazepines were the most commonly used (23.5%), followed by diphenhydramine (8.3%), trazodone (6.6%), benzodiazepine receptor agonists (6.4%), and atypical antipsychotics (6.3%). A fall occurred in 2,427 hospitalizations (1.1%). The rate of falls per 1,000 hospital days was greater among hospitalizations with exposure to each of the medications of interest, compared to unexposed: 3.6 versus 1.7 for benzodiazepines (adjusted hazard ratio [aHR] 1.8, 95%CI 1.6–1.9); 5.4 versus 1.8 for atypical antipsychotics (aHR 1.6, 95%CI 1.4–1.8); 3.0 versus 2.0 for benzodiazepine receptor agonists (aHR 1.5, 95%CI 1.3–1.8); 3.3 versus 2.0 for trazodone (aHR 1.2, 95%CI 1.1–1.5); and 2.5 versus 2.0 for diphenhydramine (aHR 1.2, 95%CI 1.03–1.5). Conclusions In this large cohort of hospitalizations at an academic medical center, we found an association between each of the sedating medications examined and in-hospital falls. Benzodiazepines, benzodiazepine receptor agonists, and atypical antipsychotics had the strongest associations.

BackgroundPrognostic models help aid medical decision-making. Various prognostic models are available via websites such as MDCalc, but these models typically predict one outcome, for example, stroke risk. Each model requires individual predictors, for example, age, lab results and comorbidities. There is no clinical tool available to predict multiple outcomes from a list of common medical predictors.ObjectiveIdentify a constrained set of outcome-agnostic predictors.MethodsWe proposed a novel technique aggregating the standardised mean difference across hundreds of outcomes to learn a constrained set of predictors that appear to be predictive of many outcomes. Model performance was evaluated using the constrained set of predictors across eight prediction tasks. We compared against existing models, models using only age/sex predictors and models without any predictor constraints.ResultsWe identified 67 predictors in our constrained set, plus age/sex. Our predictors included illnesses in the following categories: cardiovascular, kidney/liver, mental health, gastrointestinal, infectious and oncologic. Models developed using the constrained set of predictors achieved comparable discrimination compared with models using hundreds or thousands of predictors for five of the eight prediction tasks and slightly lower discrimination for three of the eight tasks. The constrained predictor models performed as good or better than all existing clinical models.ConclusionsIt is possible to develop models for hundreds or thousands of outcomes that use the same small set of predictors. This makes it feasible to implement many prediction models via a single website form. Our set of predictors can also be used for future models and prognostic model research.

While seismic isolation is one of the principal approaches used to mitigate the risks associated with earthquake ground shaking, it has found only limited application in the construction of nuclear power plants (NPPs). As a new application, it is necessary to understand how the overall process works and figure out potential difficulties in all stages of managing isolated NPPs. Several manufacturers, experts, and representatives from engineering firms were contacted and interviewed to better understand potential difficulties in the application of seismic isolation to NPPs. In addition to this firsthand knowledge, studies and research conducted in the area of radiation exposure and the area of general durability are reviewed. According to these materials, this paper summarizes some issues related to the durability of the isolators, radiation, and other environmental effects on devices and raises some understanding and special issues in the planning, design, analysis, procurement, installation, operations, and maintenance stages of managing a seismically isolated NPP. These topics are expected to provide a certain guiding significance on future application of seismic isolation for NPPs.

The main focus of this paper was to examine some of the principal advantages and disadvantages cited for the application of seismic isolation to nuclear power facilities. This discussion is followed by an examination of the potential relative impacts on cost and schedule of a conventional fixed‐base design approach vs one based on seismic isolation. This examination considers issues associated with planning, design, operation, and decommission. Some of the challenges related to design and maintenance (during normal operations and following a significant earthquake) are then discussed, and specific research and development topics are identified that are necessary to allow seismic isolation to be pursued with confidence. Finally, overall conclusions and recommendations are offered. The use of seismic isolation has increased gradually around the world. It would be prudent to consider more fully the potential benefits, costs, and impediments associated with widespread use of seismic in the nuclear industry. This paper examine some of the principal advantages and disadvantages cited for the application of seismic isolation to nuclear power facilities, and introduce an examination of the potential relative impacts on cost and schedule of a conventional fixed‐base design approach versus one based on seismic isolation.

Sustainable structures are critical for addressing global climate change. Hence, their structural resilience or ability to recover from natural events must be considered comprehensively. Green roofs are a widely used sustainable feature that improve the environment while providing excellent occupant amenity. To expand their usage, their inherent damping and layout sensitivity to seismic performance are investigated in this study. The soil of a green roof can serve as a damper to dissipate the energy generated by earthquakes or other dynamic events. Results of preliminary analysis show that a green roof soil can increase localized damping by 2.5% under both dry and saturated conditions. Based on these findings, nonlinear time-history analyses are conducted on a three-story building in SAP2000 to monitor the structural behavior with and without a green roof. The increased damping in the green roof soil is beneficial to the structural performance, i.e., it reduces the building displacement and acceleration by 10% and 12%, respectively. Additionally, certain configurations are more effective and beneficial to the structural response than others, which suggests the possibility of design optimization. Based on the findings of this study, new methods of modeling and considering green roofs in structural design are established.

Background Surgeries and other procedures can influence the risk of death in hospital. All published scales that predict post-operative death risk require clinical data and cannot be measured using administrative data alone. This study derived and internally validated an index that can be calculated using administrative data to quantify the independent risk of hospital death after a procedure. Methods For all patients admitted to a single academic centre between 2004 and 2009, we estimated the risk of all-cause death using the Kaiser Permanente Inpatient Risk Adjustment Methodology (KP-IRAM). We determined whether each patient underwent one of 503 commonly performed therapeutic procedures using Canadian Classification of Interventions codes and whether each procedure was emergent or elective. Multivariate logistic regression modeling was used to measure the association of each procedure-urgency combination with death in hospital independent of the KP-IRAM risk of death. The final model was modified into a scoring system to quantify the independent influence each procedure had on the risk of death in hospital. Results 275 460 hospitalizations were included (137,730 derivation, 137,730 validation). In the derivation group, the median expected risk of death was 0.1% (IQR 0.01%-1.4%) with 4013 (2.9%) dying during the hospitalization. 56 distinct procedure-urgency combinations entered our final model resulting in a Procedural Index for Mortality Rating (PIMR) score values ranging from -7 to +11. In the validation group, the PIMR score significantly predicted the risk of death by itself (c-statistic 67.3%, 95% CI 66.6-68.0%) and when added to the KP-IRAM model (c-index improved significantly from 0.929 to 0.938). Conclusions We derived and internally validated an index that uses administrative data to quantify the independent association of a broad range of therapeutic procedures with risk of death in hospital. This scale will improve risk adjustment when administrative data are used for analyses.

Sustainability addresses the need to reduce the structure’s impact on the environment but does not reduce the environment’s impact on the structure. To explore this relationship, this study focuses on quantifying the impact of green roofs or vegetated roofs on seismic responses such as story displacements, interstory drifts, and floor level accelerations. Using an archetype three-story steel moment frame, nonlinear time history analyses are conducted in OpenSees for a shallow and deep green roof using a suite of ground motions from various distances from the fault to identify key trends and sensitivities in response.